title: Molecular karyotypes of Hodgkin and Reed-Sternberg cells at disease onset reveal distinct copy number alterations in chemosensitive versus refractory Hodgkin lymphoma.
abstract: OBJECTIVE
  To determine the recurring DNA copy number alterations (CNA) in classical Hodgkin lymphoma (HL) by microarray-based comparative genomic hybridization (aCGH) using laser capture microdissected CD30(+) Hodgkin and Reed-Sternberg (HRS) cells.
  
  
  METHODS
  Archived tissues from 27 CD30(+) HL plus control samples were analyzed by DNA microarrays. The HL molecular karyotypes were compared with the genomic profiles of germinal center B cells and treatment outcome (chemotherapy responsive vs. primary refractory disease).
  
  
  RESULTS
  Gains and losses observed in more than 35% of HL samples were localized to 22 and 12 chromosomal regions, respectively. Frequent gains (>65%) were associated with growth and proliferation, NF-κB activation, cell-cycle control, apoptosis, and immune and lymphoid development. Frequent losses (>40%) observed encompassed tumor suppressor genes (SPRY1, NELL1, and ID4, inhibitor of DNA binding 4), transcriptional repressors (TXNIP, thioredoxin interacting protein), SKP2 (S-phase kinase-associated protein 2; ubiquitin ligase component), and an antagonist of NF-κB activation (PPARGC1A). In comparison to the germinal center profiles, the most frequent imbalances in HL were losses in 5p13 (AMACR, GDNF, and SKP2), and gains in 7q36 (SHH, sonic hedgehog homolog) and 9q34 (ABL1, CDK9, LCN2, and PTGES). Gains (>35%) in the HL chemoresponsive patients housed genes known to regulate T-cell trafficking or NF-κB activation (CCL22, CX3CL1, CCL17, DOK4, and IL10), whereas the refractory samples showed frequent loss of 4q27 (interleukin; IL21/IL2) and 17p12, and gain of 19q13.3 (BCL3/RELB).
  
  
  CONCLUSIONS
  We identified nonrandom CNAs in the molecular karyotypes of classical HL. Several recurring genetic lesions correlated with disease outcome. These findings may be useful prognostic markers in the counseling and management of patients and for the development of novel therapeutic approaches in primary refractory HL.
authors.affiliation: Cytogenetics Laboratory, Department of Hematology/Stem Cell Transplantation, City of Hope, Duarte, California 91010, USA.
authors.forename: Marilyn L
authors.initials: ML
authors.lastname: Slovak
authors.forename: Victoria
authors.initials: V
authors.lastname: Bedell
authors.forename: Ya-Hsuan
authors.initials: YH
authors.lastname: Hsu
authors.forename: Dolores B
authors.initials: DB
authors.lastname: Estrine
authors.forename: Norma J
authors.initials: NJ
authors.lastname: Nowak
authors.forename: Maria L
authors.initials: ML
authors.lastname: Delioukina
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Weiss
authors.forename: David D
authors.initials: DD
authors.lastname: Smith
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Forman
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D055088:Early Detection of Cancer; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006689:Hodgkin Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007621:Karyotyping / Q000379:methods; D008297:Male; D008875:Middle Aged; D016539:Reed-Sternberg Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D055815:Young Adult